Pyrimidine derivatives as selective inhibitors of COX-2

ABSTRACT

The invention provides the compounds of formula (I) 
                         
and pharmaceutically acceptable salts thereof, in which:
     R 1  and R 2  are independently selected from H, or C 1-6 alkyl;   R 3  is selected from the group consisting of C 1-6 alkyl, NH 2  and R 6 CONH;   R 4  is H or C 1-6 alkyl;   R 5  is selected from the group consisting of CH 2 F, CHF 2 , CF 3 CH 2 , CF 3 CHF and CF 3 CF 2 ;   A is a 5- or 6-membered aryl, or a 5- or 6-membered aryl substituted by one or more R 7 ;   R 6  is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylOC 1-6 alkyl, phenyl, HO 2 CC 1-6 alkyl, C 1-6 alkylOCOC 1-6 alkyl, C 1-6 alkylOCO, H 2 NC 1-6 alkyl, C 1-6 alkylOCONHC 1-6 alkyl and C 1-6 alkylCONHC 1-6 alkyl;   R 7  is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more F, C 1-6 alkoxy, C 1-6 alkoxy substitued by one or more F, SO 2 NH 2  or SO 2 C 1-6 alkyl; and   n is 1 to 4.   
     Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/GB02/03601, filed 5 Aug.2002, which claims Priority to GB Application Serial No. 0119477.8,filed 9 Aug. 2001.

This invention relates to pyrimidine derivatives, to processes for theirpreparation, to pharmaceutical compositions containing them and to theiruse in medicine.

The enzyme cyclooxygenase (COX) has recently been discovered to exist intwo isoforms, COX-1 and COX-2. COX-1 corresponds to the originallyidentified constitutive enzyme while COX-2 is rapidly and readilyinducible by a number of agents including mitogens, endotoxin, hormones,cytokines and growth factors. Prostaglandins generated by the action ofCOX have both physiological and pathological roles. It is generallybelieved that COX-1 is largely responsible for the importantphysiological functions such as maintenance of gastrointestinalintegrity and renal blood flow. In contrast the inducible form, COX-2,is believed to be largely responsible for the pathological effects ofprostaglandins where rapid induction of the enzyme occurs in response tosuch agents as inflammatory agents, hormones, growth factors andcytokines. A selective inhibitor of COX-2 would therefore haveanti-inflammatory, anti-pyretic and analgesic properties, without thepotential side effects associated with inhibition of COX-1. We have nowfound a novel group of compounds which are both potent and selectiveinhibitors of COX-2.

The invention thus provides the compounds of formula (I)

and pharmaceutically acceptable salts thereof, in which:

-   R¹ and R² are independently selected from H, or C₁₋₆alkyl;-   R³ is selected from the group consisting of C₁₋₆alkyl, NH₂ and    R⁶CONH;-   R⁴ is H or C₁₋₆alkyl;-   R⁵ is selected from the group consisting of CH₂F, CHF₂, CF₃CH₂,    CF₃CHF and CF₃CF₂;-   A is a 5- or 6-membered aryl, or a 5- or 6-membered aryl substituted    by one or more R⁷;-   R⁶ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkylOC₁₋₆alkyl, phenyl, HO₂CC₁₋₆alkyl,    C₁₋₆alkylOCOC₁₋₆alkyl, C₁₋₆alkylOCO, H₂NC₁₋₆alkyl,    C₁₋₆alkylOCONHC₁₋₆alkyl and C₁₋₆alkylCONHC₁₋₆alkyl;-   R⁷ is selected from the group consisting of halogen, C₁₋₆alkyl,    C₁₋₆alkyl substituted by one or more F, C₁₋₆alkoxy, C₁₋₆alkoxy    substituted by one or more F, SO₂NH₂ or SO₂C₁₋₆alkyl; and-   n is 0 or 1 to 4.

In a further aspect the invention provides the compounds of formula (I)

and pharmaceutically acceptable salts thereof, in which:

-   R¹ and R² are independently selected from H, or C₁₋₆alkyl;-   R³ is selected from the group consisting of C₁₋₆alkyl, NH₂ and    R⁶CONH;-   R⁴ is H or C₁₋₆alkyl;-   R⁵ is selected from the group consisting of CH₂F, CHF₂, CF₃CH₂,    CF₃CHF and CF₃CF₂;-   A is a 5- or 6-membered aryl, or a 5- or 6-membered aryl substituted    by one or more R⁷;-   R⁶ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkylOC₁₋₆alkyl, phenyl, HO₂CC₁₋₆alkyl,    C₁₋₆alkylOCOC₁₋₆alkyl, C₁₋₆alkylOCO, H₂NC₁₋₆alkyl,    C₁₋₆alkylOCONHC₁₋₆alkyl and C₁₋₆alkylCONHC₁₋₆alkyl;-   R⁷ is selected from the group consisting of halogen, C₁₋₆alkyl,    C₁₋₆alkyl substituted by one or more F, C₁₋₆alkoxy, C₁₋₆alkoxy    substituted by one or more F, SO₂NH₂ or SO₂C₁₋₆alkyl; and-   n is 1 to 4.

Suitable pharmaceutically acceptable salts include acid addition saltsformed with the amine functionality NR⁴(CR¹R²)_(n)-A. Pharmaceuticallyacceptable salts include those described by Berge, Bighley andMonkhouse, J. Pharm. Sci., 1977, 66, 1–19. Such salts may be formed frominorganic and organic acids. Representative examples thereof includemaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicyclic, methanesulfonic, p-toluenesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric,gluconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, taurocholic, benzenesulfonic, hydrochloric,hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that, for pharmaceutical use, the salts referredto above will be the physiologically acceptable salts, but other saltsmay find use, for example in the preparation of compounds of formula (I)and the physiologically acceptable salts thereof.

The term halogen is used to represent fluorine, chlorine, bromine oriodine.

The term ‘alkyl’ as a group or part of a group means a straight orbranched chain alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl or t-butyl group.

The term 5-membered aryl means an aryl selected from the following:

The term 6-membered aryl means aryl selected from:

It will be appreciated by those skilled in the art that when R¹ and R²in formula (I) are different the corresponding compounds contain atleast one chiral centre, by virtue of the asymmetric carbon atom definedthereby, and that such compounds exist in the form of a pair of opticalisomers (i.e. enantiomers).

It is to be understood that the present invention encompasses allisomers of the compounds of formula (I) and their pharmaceuticallyacceptable derivatives, including all geometric, tautomeric and opticalforms, and mixtures thereof (e.g. racemic mixtures).

In one aspect of the invention R¹ and R² are both H.

In another aspect of the invention R³ is C₁₋₆alkyl, such as C₁₋₃alkyl(e.g. methyl).

In another aspect of the invention R⁴ is H or C₁₋₃alkyl, such as methyl.

In another aspect of the invention R⁵ is CH₂F or CHF₂.

In another aspect of the invention R⁶ is selected from the groupconsisting of C₁₋₆alkyl (e.g. ethyl), phenyl or aminomethyl.

In another aspect of the invention A is selected from

In another aspect of the invention R⁷ is halogen (e.g. F) or C₁₋₆alkoxy,such as C₁₋₃alkoxy (e.g. methoxy).

In another aspect of the invention n is 1 to 3 (e.g. 1).

In another aspect the invention provides the following compound:4-[4-(methylsulfonyl)phenyl]-N-(phenylmethyl)-6-(fluoromethyl)pyrimidin-2-amine.

It is to be understood that the invention covers all combinations ofparticular aspects of the invention as described hereinabove.

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compound of formula (I) may be used for preparingthe more pure forms used in pharmaceutical compositions. Although thepurity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are available incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are recrysallised from organic solvents, solvent of recrystallisationmay be present in the crystalline product. This invention includeswithin its scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or recrystallised from solvents containingwater. In such cases water of hydration may be formed. This inventionincludes within its scope stoichiometric hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope all thepolymorphic forms of the compounds of formula (I).

Compounds of the invention are potent and selective inhibitors of COX-2.This activity is illustrated by their ability to selectively inhibitCOX-2 over COX-1.

In view of their selective COX-2 inhibitory activity, the compounds ofthe present invention are of interest for use in human and veterinarymedicine, particularly in the treatment of the pain (both chronic andacute), fever and inflammation of a variety of conditions and diseasesmediated by COX-2. Such conditions and diseases are well known in theart and include rheumatic fever; symptoms associated with influenza orother viral infections, such as the common cold; lower back and neckpain; headache; toothache; sprains and strains; myositis;sympathetically maintained pain; synovitis; arthritis, includingrheumatoid arthritis; degenerative joint diseases, includingosteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis;skin related conditions, such as psoriasis, eczema, burns anddermatitis; injuries, such as sports injuries and those arising fromsurgical and dental procedures.

The compounds of the invention are also useful for the treatment ofneuropathic pain. Neuropathic pain syndromes can develop followingneuronal injury and the resulting pain may persist for months or years,even after the original injury has healed. Neuronal injury may occur inthe peripheral nerves, dorsal roots, spinal cord or certain regions inthe brain. Neuropathic pain syndromes are traditionally classifiedaccording to the disease or event that precipitated them. Neuropathicpain syndromes include: diabetic neuropathy; sciatica; non-specificlower back pain; multiple sclerosis pain; fibromyalgia; HIV-relatedneuropathy; neuralgia, such as post-herpetic neuralgia and trigeminalneuralgia; and pain resulting from physical trauma, amputation, cancer,toxins or chronic inflammatory conditions. These conditions aredifficult to treat and although several drugs are known to have limitedefficacy, complete pain control is rarely achieved. The symptoms ofneuropathic pain are incredibly heterogeneous and are often described asspontaneous shooting and lancinating pain, or ongoing, burning pain. Inaddition, there is pain associated with normally non-painful sensationssuch as “pins and needles” (paraesthesias and dysesthesias), increasedsensitivity to touch (hyperesthesia), painful sensation followinginnocuous stimulation (dynamic, static or thermal allodynia), increasedsensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia),continuing pain sensation after removal of the stimulation (hyperpathia)or an absence of or deficit in selective sensory pathways (hypoalgesia).

The compounds of the invention are also useful for the treatment ofother conditions mediated by COX-2.

For example, the compounds of the invention inhibit cellular andneoplastic transformation and metastatic tumour growth and hence areuseful in the treatment of certain cancerous diseases, such as coloniccancer and prostate cancer. The compounds of the invention are alsouseful in reducing the number of adenomatous colorectal polyps and thusreduce the risk of developing colon cancer. The compounds of theinvention are also useful in the treatment of cancer associated withoverexpression of HER-2/neu, in particular breast cancer.

Compounds of the invention also prevent neuronal injury by inhibitingthe generation of neuronal free radicals (and hence oxidative stress)and therefore are of use in the treatment of stroke; epilepsy; andepileptic seizures (including grand mal, petit mal, myoclonic epilepsyand partial seizures).

Compounds of the invention also inhibit prostanoid-induced smooth musclecontraction and hence are of use in the treatment of dysmenorrhoea andpremature labour.

Compounds of the invention are also useful in the treatment of liverdisease, such as inflammatory liver disease, for example chronic viralhepatitis B, chronic viral hepatitis C, alcoholic liver injury, primarybiliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitisand liver transplant rejection.

Compounds of the invention inhibit inflammatory processes and thereforeare of use in the treatment of asthma, allergic rhinitis and respiratorydistress syndrome; gastrointestinal conditions such as inflammatorybowel disease, Crohn's disease, gastritis, irritable bowel syndrome andulcerative colitis; and the inflammation in such diseases as vasculardisease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia,Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis,multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome,polymyositis, gingivitis, conjunctivitis and myocardial ischemia.

Compounds of the invention are also useful in the treatment ofophthalmic diseases such as retinitis, retinopathies, uveitis and ofacute injury to the eye tissue.

Compounds of the invention are also useful for the treatment ofcognitive disorders such as dementia, particularly degenerative dementia(including senile dementia, Alzheimer's disease, Pick's disease,Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease),and vascular dementia (including multiinfarct dementia), as well asdementia associated with intracranial space occupying lesions, trauma,infections and related conditions (including HIV infection), metabolism,toxins, anoxia and vitamin deficiency; and mild cognitive impairmentassociated with ageing, particularly Age Associated Memory Impairment.

Compounds of the invention are also useful in the treatment of disordersameliorated by a gastroprokinetic agent. Disorders ameliorated bygastroprokinetic agents include ileus, for example post-operative ileusand ileus during sepsis; gastroesophageal reflux disease (GORD, or itssynonym GERD); gastroparesis, such as diabetic gastroparesis; and otherfunctional bowel disorders, such as non-ulcerative dyspepsia (NUD) andnon-cardiac chest pain (NCCP).

According to a further aspect of the invention, we provide a compound offormula (I) or a pharmaceutically acceptable salt thereof for use inhuman or veterinary medicine.

According to another aspect of the invention, we provide a compound offormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of a condition which is mediated by COX-2.

According to a further aspect of the invention, we provide a method oftreating a human or animal subject suffering from a condition which ismediated by COX-2 which comprises administering to said subject aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt.

According to a further aspect of the invention, we provide a method oftreating a human or animal subject suffering from an inflammatorydisorder, which method comprises administering to said subject aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

According to another aspect of the invention, we provide the use of acompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a therapeutic agent for the treatment of acondition which is mediated by COX-2.

According to another aspect of the invention, we provide the use of acompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a therapeutic agent for the treatment of aninflammatory disorder.

It is to be understood that reference to treatment includes bothtreatment of established symptoms and prophylactic treatment, unlessexplicitly stated otherwise.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more other therapeuticagents. Examples of suitable agents for adjunctive therapy include a5HT₁ agonist, such as a triptan (e.g. sumatriptan or naratriptan); anadenosine Al agonist; an EP ligand (e.g. an EP4 antagonist); an NMDAmodulator, such as a glycine antagonist; a sodium channel blocker (e.g.lamotrigine); a substance P antagonist (e.g. an NK₁ antagonist); acannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; aleukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentinand related compounds; a tricyclic antidepressant (e.g. amitryptilline);a neurone stabilising antiepileptic drug; a mono-aminergic uptakeinhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; anitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOSinhibitor; an inhibitor of the release, or action, of tumour necrosisfactor α; an antibody therapy, such as a monoclonal antibody therapy; anantiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or animmune system modulator (e.g. interferon); an opioid analgesic; a localanaesthetic; a stimulant, including caffeine; an H₂-antagonist (e.g.ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g.aluminium or magnesium hydroxide; an antiflatulent (e.g. simethicone); adecongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine,oxymetazoline, epinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxyephedrine); an antitussive (e.g. codeine,hydrocodone, carmiphen, carbetapentane, or dextramethorphan); adiuretic; or a sedating or non-sedating antihistamine. It is to beunderstood that the present invention covers the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in combinationwith one or more other therapeutic agents.

The compounds of formula (I) and their pharmaceutically acceptable saltsare conveniently administered in the form of pharmaceuticalcompositions. Thus, in another aspect of the invention, we provide apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof adapted for use in human orveterinary medicine. Such compositions may conveniently be presented foruse in conventional manner in admixture with one or more physiologicallyacceptable carriers or excipients.

The compounds of formula (I) and their pharmaceutically acceptable saltsmay be formulated for administration in any suitable manner. They may,for example, be formulated for topical administration or administrationby inhalation or, more preferably, for oral, transdermal or parenteraladministration. The pharmaceutical composition may be in a form suchthat it can effect controlled release of the compounds of formula (I)and their pharmaceutically acceptable salts.

For oral administration, the pharmaceutical composition may take theform of, for example, tablets (including sub-lingual tablets), capsules,powders, solutions, syrups or suspensions prepared by conventional meanswith acceptable excipients.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

For parenteral administration, the pharmaceutical composition may begiven as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilising and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative.

Alternatively for parenteral administration the active ingredient may bein powder form for reconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

As stated above, the compounds of the invention may also be used incombination with other therapeutic agents. The invention thus provides,in a further aspect, a combination comprising a compound of formula (I)or a pharmaceutically acceptable salt thereof together with a furthertherapeutic agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable saltthereof is used in combination with a second therapeutic agent activeagainst the same disease state the dose of each compound may differ fromthat when the compound is used alone. Appropriate doses will be readilyappreciated by those skilled in the art.

A proposed daily dosage of a compound of formula (I) for the treatmentof man is 0.01 mg/kg to 500 mg/kg, such as 0.05 mg/kg to 100 mg/kg, e.g.0.1 mg/kg to 50 mg/kg, which may be conveniently administered in 1 to 4doses. The precise dose employed will depend on the age and condition ofthe patient and on the route of administration. Thus, for example, adaily dose of 0.25 mg/kg to 10 mg/kg may be suitable for systemicadministration.

Compounds of formula (I) and pharmaceutically acceptable salts thereofmay be prepared by any method known in the art for the preparation ofcompounds of analogous structure.

Compounds of formula (I) and pharmaceutically acceptable salts thereofmay be prepared by a process which comprises:

-   reacting an amine HNR⁴(CR¹R²)_(n)-A of formula (II) or a protected    derivative thereof with a compound of formula (III)

and thereafter and if necessary,

-   interconverting a compound of formula (I) into another compound of    formula (I); and/or-   deprotecting a protected derivative of a compound of formula (I).

The overall synthesis of a compound of formula (I) is shown in Scheme 1below in which, R¹, R², R⁴, R⁵, n and A are as defined in formula (I)above unless otherwise stated, R³ is C₁₋₆-alkyl; MTBE is methyl t-butylether; and alkyl is a straight or branched chain alkyl group, forexample a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butylgroup.

Referring to Scheme 1, the treatment of compounds of formula (III) withan amine of formula (II) is conveniently carried out in a solvent, suchas nitrile (e.g. methylnitrile) and at elevated temperature (e.g. fromabout 50° C. to reflux). An excess of the amine may be used in place ofthe solvent.

Alternatively, the treatment of compounds of formula (III) with an amineof formula (III) is conveniently carried out in a solvent, such as atertiary amine (e.g. NMP), and at between ambient and elevatedtemperature (e.g. ambient temperature). Use of, for example, NMP assolvent has the advantage that after completion of the reaction thedesired compound of formula (I) may be precipitated from the reactionmixture by the addition of water, allowing for easier isolation andpurification.

Conveniently the oxidation shown in Scheme 1 is effected using amonopersulfate compound, such as potassium peroxymonosulfate (known asOxone™) and the reaction is carried out in a solvent, such as an aqueousalcohol, (e.g. aqueous methanol), and at between −78° C. and ambienttemperature.

Alternatively, the oxidation shown in Scheme 1 may be effected usinghydrogen peroxide in the presence of catalytic sodium tungstatedihydrate. The reaction may be carried out in a solvent such as aceticacid and at between ambient temperature and reflux (e.g. 50° C.).

Referring to Scheme 1, the cyclisation of diones of formula (VI) to givethe corresponding pyrimidines of formula (IV) is conveniently carriedout employing a thioronium salt such as a 2-methyl-2-thiopseudoureasulfate and under reflux.

It will be appreciated by those skilled in the art that certain of theprocedures described in Scheme 1 for the preparation of compounds offormula (I) or intermediates thereto may not be applicable to some ofthe possible substituents.

It will be further appreciated by those skilled in the art that it maybe necessary or desirable to carry out the transformations described inScheme 1 in a different order from that described, or to modify one ormore of the transformations, to provide the desired compound of formula(I).

In one variation of Scheme 1 (Scheme 1A), compounds of formula (III)wherein R³ is C₁₋₆alkyl or NH₂ may be prepared by oxidising a compoundof formula (IV)A:

under oxidation conditions described hereinabove. Compounds of formula(IV)A may be prepared according to the general procedures of Scheme 1 byemploying sulfonyl derivatives in place of the corresponding sulfidecompounds of formulae (VI) and (VII).

In another variation of scheme 1 (scheme 1 B), compounds of formula (I)wherein R⁴ is H may be prepared from the corresponding formamylderivative, as illustrated below.

It will be appreciated by those skilled in the art that compounds offormula (I) may be prepared by interconversion, utilising othercompounds of formula (I) as precursors. Suitable interconversions, suchas alkylations, are well known to those skilled in the art and aredescribed in many standard organic chemistry texts, such as ‘AdvancedOrganic Chemistry’ by Jerry March, fourth edition (Wiley, 1992),incorporated herein by reference. For example, compounds of formula (I)wherein R⁴ is C₁₋₆-alkyl may be prepared by alkylating the correspondingcompound of formula (I) wherein R⁴ is H.

Acylation of compounds of formula (I) wherein R³ is NH₂, to providecompounds of formula (I) wherein R³ is R⁶CONH, may be carried out byconventional means, for example by employing conventional acylatingagents such as those described in ‘Advanced Organic Chemistry’, pp417–424, incorporated herein by reference.

As will be appreciated by those skilled in the art it may be necessaryor desirable at any stage in the synthesis of compounds of formula (I)to protect one or more sensitive groups in the molecule so as to preventundesirable side reactions. The protecting groups used in thepreparation of compounds of formula (I) may be used in conventionalmanner. See, for example, those described in ‘Protective Groups inOrganic Synthesis’ by Theodora W Green and Peter G M Wuts, secondedition, (John Wiley and Sons, 1991), incorporated herein by reference,which also describes methods for the removal of such groups.

Amines of formula (II) are either known compounds or may be prepared byliterature methods, such as those described in ‘Comprehensive OrganicTransformations: a guide to functional group preparations’ by RichardLarock (VCH, 1989), incorporated herein by reference.

Thioronium salts of formula (V) are either known compounds or may beprepared by literature methods, such as those described in A H Owens etal, Eur J Med Chem, 1988, 23(3), 295–300, incorporated herein byreference.

Acetophenones of formula (VII) are either known compounds or may beprepared by conventional chemistry.

Certain intermediates described above are novel compounds, and it is tobe understood that all novel intermediates herein form further aspectsof the present invention. Compounds of formulae (III) and (IV) are keyintermediates and represent a particular aspect of the presentinvention.

Conveniently, compounds of the invention are isolated following work-upin the form of the free base. Pharmaceutically acceptable acid additionsalts of the compounds of the invention may be prepared usingconventional means.

Solvates (e.g. hydrates) of a compound of the invention may be formedduring the work-up procedure of one of the aforementioned process steps.

The Example which follows illustrates the invention but does not limitthe invention in any way.

EXAMPLE 14-[4-(Methylsulfonyl)phenyl]-N-(Phenylmethyl)-6(fluoromethyl)pyrimidin-2-amine

LC/MS: retention time 4.2 min; MH+372

4-[4-(methylsulfonyl)phenyl]-N-(Phenylmethyl)-6-(fluoromethyl)pyrimidin-2-amine

Biological Data

Microsomal Assay

Inhibitory activity against microsomal h-COX2 was assessed against amicrosomal preparation from baculovirus infected SF9 cells. An aliquotof microsomal preparation was thawed slowly on ice and a 1/40,000dilution prepared from it into the assay buffer (sterile water, degassedwith argon containing 100 mM HEPES (pH 7.4), 10 mM EDTA (pH7.4), 1 mMphenol, 1 mM reduced glutathione, 20 mg/ml gelatin and 0.001 mMHematin). Once diluted the enzyme solution was then sonicated for 5seconds (Branson sonicator, setting 4, 1 cm tip) to ensure a homogeneoussuspension. 155 μl enzyme solution was then added to each well of a96-well microtitre plate containing either 5111 test compound(40×required test concentration) or 5 μl DMSO for controls. Plates werethen mixed and incubated at room temperature for 1 hour. Following theincubation period, 40 μl of 0.5 μM arachidonic acid was added to eachwell to give a final concentration of 0.1 μM. Plates were then mixed andincubated for exactly 10 minutes (room temperature) prior to addition of25 μl 1M HCl (hydrochloric acid) to each well to stop the reaction. 25μl of 1M NaOH (sodium hydroxide) was then added to each well toneutralise the solution prior to determination of PGE₂ levels by enzymeimmunoassay (EIA).

The following IC₅₀ value for inhibition of COX-2 and COX-1 were obtainedfrom the microsomal assay for compounds of the invention:

Example No. COX-2: IC₅₀ (nM) COX-1: IC₅₀ (nM) 1 22 17,700

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, in which: R¹ and R² areindependently selected from H, or C₁₋₆alkyl; R³ is selected from thegroup consisting of C₁₋₆alkyl, NH₂ and R⁶CONH; R⁴ is H or C₁₋₆alkyl; R⁵is selected from the group consisting of CH₂F, CHF₂, CF₃CH₂, CF₃CHF andCF₃CF₂; A is a 5- or 6-membered aryl, or a 5- or 6-membered arylsubstituted by one or more R⁷; R⁶ is selected from the group consistingof H, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylOC₁₋₆alkyl, phenyl, HO₂CC₁₋₆alkyl,C₁₋₆alkyOCOC₁₋₆alkyl C₁₋₆alkylOCO, H₂NC₁₋₆alkyl, C₁₋₆alkylOCONHC₁₋₆alkyland C₁₋₆alkylCONHC₁₋₆alkyl; R⁷ is selected from the group consisting ofhalogen, C₁₋₆-alkyl, C₁₋₆alkyl substituted by one or more F, C₁₋₆alkoxy,C₁₋₆alkoxy substituted by one or more F, SO₂NH₂ or SO₂C₁₋₆alkyl; and nis 1 to
 4. 2. A compound as claimed in claim 1 wherein R¹ and R² areboth H.
 3. A compound as claimed in claim 1 wherein R³ is C₁₋₆alkyl. 4.A compound as claimed in claim 1 wherein R⁴ is H or C₁₋₃alkyl.
 5. Acompound as claimed in claim 1 wherein R⁵ is CH₂F or CHF₂.
 6. A compoundas claimed in claim 1 wherein R⁶ is selected from the group consistingof C₁₋₆alkyl, phenyl or aminomethyl.
 7. A compound as claimed in claim 1wherein A is selected from


8. A compound as claimed in claim 1 wherein R⁷ Is halogen or C¹⁻⁶alkoxy.9. A compound as claimed in claim 1 wherein n is 1 to
 3. 10. A processfor the preparation of a compound as defined in claim 1 which comprises:(A), reacting an amine HNR⁴(CR¹R²)_(n)-A of formula (II) or a protectedderivative thereof with a compound of formula (III)

and thereafter and if necessary, (B), interconverting of a compound offormula (I) into another compound of formula (I); and/or (C),deprotecting a protected derivative of compound of formula (I).
 11. Apharmaceutical composition comprising a compound as defined in claim 1in admixture with one or more physiologically acceptable carriers orexcipients.
 12. A compound as claimed in claim 1 wherein R³ isC₁₋₃alkyl.
 13. A compound as claimed in claim 1 wherein R³ is methyl.14. A compound as claimed in claim 1 wherein R⁴ is H or methyl.
 15. Acompound as claimed in claim 1 wherein R⁶ is selected from the groupconsisting of ethyl, phenyl or aminomethyl.
 16. A compound as claimed inclaim 1 wherein R⁷ is F or C₁₋₃alkoxy.
 17. A compound as claimed inclaim 1 wherein R⁷ is F or methoxy.
 18. A compound as claimed in claim 1wherein n is
 1. 19.4-[4-(Methylsulfonyl)phenyl]N(phenylmethyl)-6-(fluoromethyl)pyrimidin-2-amine.20. A method of treating a human suffering from arthritis whichcomprises administering to said human an effective amount of a compoundas claimed in claim
 1. 21. A method of treating a human suffering fromrheumatoid arthritis which comprises administering to said human aneffective amount of a compound as claimed in claim
 1. 22. A method oftreating a human suffering from osteoarthritis which comprisesadministering to said human an effective amount of a compound as claimedin claim
 1. 23. A method of treating a human suffering from acute orchronic pain which comprises administering to said human an effectiveamount of a compound as claimed in claim
 1. 24. The method according toclaim 23 wherein said acute or chronic pain is lower back or neck pain.25. The method according to claim 23 wherein said acute or chronic painis neuropathic pain.
 26. The method according to claim 23 wherein saidacute or chronic pain is non-specific lower back pain.
 27. The methodaccording to claim 23 wherein said acute or chronic pain ispost-herpetic neuralgia.
 28. A method of treating a human suffering fromdysmenorrhoea which comprises administering to said human an effectiveamount of a compound as claimed in claim
 1. 29. A method of treating ahuman suffering from inflammation in migraine which comprisesadministering to said human an effective amount of a compound as claimedin claim
 1. 30. A method of treating a human suffering from inflammationin multiple sclerosis or multiple sclerosis pain which comprisesadministering to said human an effective amount of a compound as claimedin claim 1.